The prevalence of panic disorder, a debilitating mental health problem characterized by recurrent, unexpected panic attacks, is 2 times higher among females relative to males. However, research on potential explanations for this gender difference is limited. There is a prominent gender difference, favoring females over males, on anxiety sensitivity (AS;i.e., the tendency to respond fearfully to anxiety symptoms), an identified cognitive risk factor for panic pathology. Specifically, women score higher than men on measures of AS;and individuals with high AS have an increased risk of developing spontaneous panic attacks and panic disorder over 1- to 3-year follow ups. Given the tendency for high AS individuals to misinterpret bodily sensations as dangerous, the premenstrual phase of the menstrual cycle may constitute a gender-specific, cyclical stressor that contributes to the onset of maladaptive anxiety, uncued panic attacks, and panic disorder in women with a vulnerability to anxiety (i.e., high AS). Therefore, a gender-specific vulnerability-stress pathway to panic-relevant responding in women may involve an interaction between a known cognitive risk factor for panic pathology (AS) and a naturally occurring, gender-specific, internal stressor (premenstrual phase). As a first step in exploring this proposed pathway, the primary aim of this proposed R36 Mental Health Dissertation Grant to Increase Diversity project is to examine the interactive effects of AS and menstrual cycle phase (premenstrual phase vs. follicular phase) in predicting anxious- and panic-relevant responding to a laboratory biological challenge that elicits panic-relevant responses (i.e., 3 minutes of inhaling 10% CO2-enriched air). Normally menstruating adult women (N = 60) will undergo the CO2 challenge once in their premenstrual phase and once in their follicular phase. Cycle phase will be estimated by day count and ovulation kits and confirmed via progesterone assay. It is expected that women higher on AS will report greater post-challenge panic and anxiety sensations and exhibit heightened psychophysiological responses (skin conductance level) during the biological challenge when assessed in their premenstrual phase in comparison to when assessed in their follicular phase and in comparison to women lower on AS assessed in either cycle phase. A secondary aim of the proposed project is to examine the interactive effects of AS and menstrual cycle phase (premenstrual vs. follicular) on self-reported current menstrual symptom severity. Identifying gender-specific vulnerability-stress pathways will provide information pertinent to the potential etiology and maintenance of panic pathology in women and will also aid in developing prevention programs for women at high risk for panic pathology. This study's focus on identifying mechanisms that may explain vulnerability to panic pathology in women is relevant to the National Institute of Mental Health's mission to reduce the burden of mental disorders through behavioral research and to the NIMH's vision to transform the prevention of mental disorders, paving the way for a cure. PUBLIC HEALTH RELEVANCE: The 2:1 female-to-male gender difference in the prevalence of panic disorder is an important public health challenge. To further understand this gender difference, the proposed study seeks to identify etiological risk factors and/or stressors specific to women by focusing on an underlying diathesis that is elevated in women relative to men (i.e., anxiety sensitivity or fear of fear) and a cyclical, gender-specific stressor (i.e., premenstrual cycle phase) that may interact to elicit anxious responding. Results will have implications for prevention, assessment, treatment, and future research using laboratory paradigms to study panic vulnerability in women.